Over the past two decades, the concept of neurological tissue grafting or exogenous stem cell transplantation has been investigated for its potential to treat neurodegenerative disease such as Parkinson's disease. While such transplantation approaches represent a potential for a significant improvement over currently available treatments for neurological disorders, there are significant drawbacks to cell transplantation. First, ethical considerations make it difficult to obtaining enough cells with the desired characteristics to implement practical therapies. Upon transplantation the majority of cell types fail to integrate with host tissue making it necessary to implant high numbers of cells to boost the chances of integration. Furthermore, there is the chance that the implanted cells will be immunologically incompatibility with the host, the transplanted cells may result in tumor formation or pass infectious agents from the donor tissue to the host.
The presence of ongoing neurogenesis in the adult mammalian brain raises the exciting possibility that endogenous progenitor cells may be able to generate new neurons to replace cells lost through brain injury or neurodegenerative disease. Several researchers have demonstrated increased cell proliferation and the generation of new neurons in various diseased brains. Such findings have lead to the conclusion that mitotic activity persists in various regions of the adult mammal CNS.
Adult endogenous stem cells are activated in response to various injuries but their capacities to proliferate, migrate, differentiate to the appropriate cell type, make the appropriate contacts and perform the appropriate function (ie neurotransmitter release) is quite variable. This variability depends, in part on the lesion-type and the germinative zone from which they arise. Various works suggest that the ability of endogenous stem cells to proliferate, migrate, differentiate and integrate can be enhanced by various stimulation signals. For example, administration of growth factors and electrical stimulation have each been suggested to promote neurogenesis and conceivably direct the proliferation, migration, differentiation and integration of new cells in the central nervous system. However, the method of combining several different approaches simultaneously or in sequence, and device(s) to achieve this has not been previously disclosed.
Deep brain electrical stimulation (DBS) has been used as therapy for Parkisons and other disorders of the CNS including pain. Although the mechanism of action is unknown, it is believed that DBS normalizes aberrant neuronal cell activity. However, there is some evidence to suggest that applying direct current electric fields can enhance the axonal growth of a neuron (summarized in Grill et al, 2001). More recently, two studies demonstrate that electrical activity can control the genesis of new neurons from stem cells and control the patterns of growth of neurons extending from the cortex to the spinal cord (Deisseroth et al., 2004 and Salimi and Martin, 2004).
Others suggest that infusions of exogenous growth factors into the ventricles increase the proliferation of neural progenitors around the ventricle and the central canal of the spinal cord (Martens et al., 2002). Futhermore, Fallon et al (2000) describe the infusion of a growth factor to the caudate-putamen. The infusion of transforming growth factor alpha (TGFα) resulted in the proliferation, migration and integration of stem cells in to the substantia nigra of a 6-OHDA lesioned rats (Fallon 2000). Growth factors are one example of a soluble stimulation signal for neurogenesis. It is likely that a combination of extracellular signals and microenvironmental conditions may be necessary for the proliferation, differentiation, migration and integration of stem cells.
Methods such as transcranial magnetic stimulation (TMS), direct and indirect electrical stimulation have been proposed to treat a variety of disorders and conditions. The use of electrical stimulation in these methods is to drive the existing neurons for enhanced function.
Cell replacement therapy is another method for restoring functionality lost to several systems of the body due to damage, disease and or disorders of the central nervous system. Dead or dysfunctional cells in the brain or spinal cord are replaced by undifferentiated cells, such as stem cells or blast cells. These cells may be derived from cultured cells, dedifferentiated cell lines, cancer cell lines, fetal tissues or other progenitor cell types. These relatively undifferentiated cells transform themselves to replace and assume the duties of native cells lost due to disease, damage, or trauma. Accordingly, the implanted cells can assume many characteristics of the native cells that they are replacing. One method of cell replacement therapy (disclosed in U.S. Pat. No. 6,214,334 to Lee) is to implant mature neurons at the site of nerve damage. The mature neurons can develop as replacement cells for the destroyed or damaged neurons and can make necessary linkages to restore the functionality of the damaged neurons. However, the process of cell replacement therapy does not always result in full or even partial functionality of the replacement cells.
A method of cell replacement currently available for promoting recovery from damage to the CNS involves implanting stem cells within the brain or spinal cord and administering a neuronal stimulant to the cells as described in WO01/12236 to Finklestein et al. Finklestein discloses administering stem cells and neural stimulant in vivo to improve sensory, motor or cognitive abilities. In one embodiment, Finklestein discloses TMS as a neural stimulant. In another embodiment, the neural stimulant is an anti-depressant or combinations thereof. Finkelstien dose not mention the use of, or the administration of, growth factors, chemo-attractant factors or other stem cell enhancing agents. Furthermore, Finkelstien does not describe the promotion of endogenous cells for these purposes or with these stimulants.
WO96/33731 and others in its class disclose the administration of growth factors to promote the structural and functional integration of implanted, exogenous neurons or grafted tissue. Here the neurotrophic factor is administered to the CNS when the implanted neurons are optimally responsive to the factor. WO96/33731 does not describe the application of an electrical stimulation to promote the exogenous stem cells.
US2003/0088274 to Gliner et al describes electrically stimulating cells before and/or after being implanted in the nervous system of a patient to enhance the ability of cells to achieve increased functionality. In one aspect, Gliner describes electrically enhancing the achievement of full functionality of cells capable of differentiating into neurons implanted in a patient's nervous system. In another aspect, Gilner describes electrical stimulation of fully differentiated neurons implanted in patient's nervous system to promote growth and connectivity of the implanted neurons. Gliner describes applying the electrical stimulation to a defined portion of the brain where neural activity for carrying out the neural function actually occurs in the particular patient-usually the cortex. Gliner does not describe the use of electrical stimulation applied to endogenous (non-implanted) stem cell or stem cells-like populations of cell in the CNS to achieve similar functionality. Nor does Gilner describe the administration of growth factors, in addition to electrical stimulation to achieve functionality.
WO 95/13364 describes a method to treat a neurological disorder caused by lost or damaged neural cells. The invention discloses the method of administrating growth factors or genetic material to the ventricles. The administration of such agents is intended to promote the proliferation/differentiation and/or migration of the endogenous precursor cells lining the ventricle so as to replace the lost or damaged neural cells. While Wiess describes the promotion of endogenous stem cells for replacement therapy, the delivery of growth factors and genetic material is limited in delivery site (ventricles) and device (osmotic pump). Additionally, WO 95/13364 and others in its class do not disclose the use of electrical stimulation to promote the endogenous stem cells.
The aforementioned publications as well as other similar art discloses the application of soluble stem cell enhancing agents (such as growth factors) as well as electrical stimulation of stem cells to promote the proliferation, migration and integration of implanted, exogenous stem cells. However, none of the prior art mentions the combination of the two such approaches in a step-wise or simultaneous manner. Further, none describe or suggest the application of electrical signals or soluble enhancing agents to more than one CNS region to encourage proliferation, differentiation, migration or integration of stem cells.